The ideal bone graft would replace bone defects, such as those from disease or trauma, with a material that allows bone cells to grow into the affected area, thus restoring the bone to its original condition. Currently, autografts are the best material for bone repair because they are biocompatible and there is little risk of disease transfer. However, the downside of autografts is that a separate operation must be performed to remove the person's own bone. Allografts, which consist of bone from another person/cadaver, as well as xenograft, (bone from another animal species) are also available but carry the risk of immune response and disease transfer that could lead to ultimate failure.
In order to solve the problems associated with bone grafts, many researchers have tried to develop artificial substances for bone grafts. These artificial biomaterials need to possess several qualities in order to be successful. First, the material must be porous to allow room for new bone to grow into the implant site. Second, it must maintain mechanical strength similar to native bone. Finally, the artificial biomaterial needs to be osteoconductive; that is, it must allow bone cells to attach and propagate on its surface, as it resorbs.
Some of the materials that have shown promise as bone grafts include calcium phosphate ceramics such as hydroxyapatite and tricalcium phosphate. These particular ceramics are quite biocompatible because they have characteristics similar to native bone mineral. However, they are hard to shape and do not possess the same mechanical properties as bone. They are quite brittle and require extremely delicate handling when shaping or drilling to avoid breaking the material. Hydroxyapatite degrades very slowly, which inhibits new bone from forming.
Another type of material that has sparked some interest is the use of degradable polymer. Polymers easy to shape and degrade at a predictable rate, thereby allowing new bone growth to replace it. Some examples of degradable polymers are poly(glycolic acid), poly(L-lactic acid), and poly(D,L-lactic-co-glycolic acid). Although they are easily formed and have good mechanical strength, degradable polymers alone are not ideal for bone grafts because they are not very osteoconductive. New bone will not attach well or grow well into this material.
Synthetic polymers which can be used in the present invention include poly(hydroxy acids) such as poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), poly(L-lactic acid-co-glycolic acid) (PLLGA), polyanhydrides, polyorthoesters, poly(ester amides), polyamides, poly(ester ethers)polycarbonates, polyalkylenes such as polyethylene and polypropylene, polyalkylene glycols such as poly(ethylene glycol) (PEG), polyalkylene oxides such as poly(ethylene oxide) (PEO), polyalkylene terephthalates such as poly(ethylene terephthalate), polyvinyl alcohols (PVA), polyvinyl ethers, polyvinyl esters such as poly(vinyl acetate), polyvinyl halides such as poly(vinyl chloride) (PVC), polyvinylpyrrolidone, polysiloxanes, polystyrene (PS), polyurethanes, derivatized celluloses such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, polymers of acrylic acids, such as poly(methyl(meth)acrylate) (μmMA), poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate), poly(isobutyl(meth)acrylate), poly(hexyl(meth)acrylate), poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate), poly(phenyl(meth)acrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutylacrylate), poly(octadecyl acrylate) (jointly referred to herein as “polyacrylic acids”), and copolymers and mixtures thereof, polydioxanone and its copolymers, polyhydroxyalkanoates, poly(propylene fumarate), polyoxymethylene, and poloxamers.
The polymers can optionally include one or more photopolymerizable groups. The polymers can also be derivativatized. For example, the polymers can have substitutions such as alkyl groups, alkylene groups, or other chemical groups. The polymers can also be hydroxylated oxidized, or modified in some other way familiar to those skilled in the art. Blends and co-polymers of these polymers can also be used.
Preferred non-biodegradable polymers include ethylene vinyl acetate, polyacrylic acids, polyamides, and copolymers and blends thereof.
Preferred biodegradable polymers include poly(hydroxy acids) such as Poly lactic acid (PLA), poly glycolic acid (PGA), Poly lactic co-glycolic acid (PLGA), and copolymers with polyethylene glycol (PEG); polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), trimethylene carbonate, and the polymers described in Hubbell et al., U.S. Pat. Nos. 5,654,381; 5,627,233; 5,628,863; 5,567,440; and 5,567,435. In general, these materials degrade in vivo by both non-enzymatic and enzymatic hydrolysis, and by surface or bulk erosion.
Preferred water-soluble polymers include polyethylene oxides, polyethylene glycols, ethylene oxide-propylene oxide copolymers (poloxamers and poloxamines), polyvinyl alcohols, polyvinylpyrrolidones, poly(acrylic acids), and copolymers and blends thereof.
Natural polymers that can be used in the invention include polysaccharides such as alginate, dextran, and celluloses; collagens, including derivatized collagens (e.g., alkylated, hydroxylated, oxidized, or PEG-lated collagens, as well as collagens modified by other alterations routinely made by those skilled in the art); hydrophilic proteins such as albumin; hydrophobic proteins such as protamines, and copolymers and mixtures thereof. In general, these materials degrade by enzymatic hydrolysis, by exposure to water in vivo, or by surface or bulk erosion.
Preferred bioadhesive polymers include polyanhydrides and polyacrylic acids. In one embodiment, reactive groups on the polymers, for example, hydroxy, amine, carboxylic acid, thiol, anhydride, ester and vinyl groups are reacted with reactive groups on agents to be incorporated into the polymer matrix. For example, bioactive compounds such as proteins contain reactive amine groups which can be coupled with reactive carboxylic acid, ester, or anhydride groups on the polymer to form polymers that are covalently bonded to the compounds. In another embodiment, ion pairs are formed between acidic or basic groups on a polymer and basic or acidic groups on a bioactive compound to form a polymer that is ionically bonded to the compounds. Those of skill in the art can readily determine an appropriate bioactive compound and polymer to couple by forming ionic or covalent bonds, and can also readily determine appropriate reaction conditions for forming such bonds.
One factor to be considered when selecting an appropriate polymer is the time required for in vivo stability, i.e., the time in which the polymer matrix is required to degrade, in those embodiments in which the matrix is used in vivo. Preferably, the polymer matrix exhibits an in vivo stability between approximately a few minutes and one year. When used for drug delivery, the in vivo stability is preferably between a few hours and two months. When used for tissue engineering, the in vivo stability is preferably between one week and several months.
The art has used blocks of hydroxyapatite tri calcium phosphate (HA TCP) as a bone graft material. Such materials are extremely brittle and fracture when drilled or a screw is inserted. Additionally, HA TCP when used alone in blocks has limited porosity, if any, and tends to get encapsulated as a foreign body when implanted. As such, HA TCP Block is never truly integrated into the existing bone except at a very narrow margin at the surface of the block. As a result, it does not gain the strength of a graft fabricated from harvested bone.
It is possible to make a composite using a phosphate ceramic in conjunction with a degradable polymer. Small particles of ceramic can be included within the polymer scaffold material. These particles will be partially exposed on the surface of the biomaterial, thereby making the material more osteoconductive.
Most related methods for making a polymer/ceramic scaffold biomaterial use organic solvents. This can be highly disadvantageous because some residual solvent may remain in the material. Almost all organic solvents are detrimental to cell and tissue growth. Also, it has been noted that these processes may actually leave behind a thin film of polymer that coats the ceramic particles that are supposed to be exposed on the surface. This unintentional thin film disrupts the osteoconductive nature of the ceramic portion of these biomaterials.
Shaping polymer base scaffolds has presented significant challenges because the use of mechanical cutting and shaping devices such as drills or saws melts the polymer distorting the surface. In particular, the exposed hydroxyapatite is occluded rendering the material a less effective bone replacement. Conventional abrasives such as aluminum oxide or carborundum generally cannot be used because they will contaminate the scaffold.
The invention disclosed herein addresses the problems by describing a polymer/ceramic biomaterial comprised of degradable polymer and ceramic wherein the ceramic is highly exposed on the surface of the biomaterial and the biomaterial is fabricated with no use of organic solvents. The materials are infused with collagen, providing further attachment point for osteogenic cells. Furthermore, an additional layer of a mineral, such as apatite, can be coated on the surface of the biomaterial in an adherent, fast, uniform fashion. Finally, granules of the polymer/ceramic biomaterial with additional ceramic coating can be fabricated.
All references cited within this application are expressly incorporated by reference in their entirety.